Highly Efficient Diastereoselective Reduction of α-Fluoroimines

Malamakal, Roy M.; Hess, Whitney R.; Davis, Todd A.

doi:10.1021/ol100647b

Cited by 29 publications

(10 citation statements)

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“…Remarkably, the phenyl α-chloroacetate smoothly underwent sequential hydrosilylation/C–H silylation of substrates bearing ortho- isopropyl, tert -butyl, and phenyl moieties (Scheme d). These are surprising results because only a few successful chelation-controlled nucleophilic additions to α-halo carbonyl or imino electrophiles have been reported owing to the relatively low basicity of halogens, and all of these prior examples utilized α-fluoro carbonyl derivatives . Although the Walsh group demonstrated diastereoselective chelation-controlled addition of carbon nucleophiles to α-chloro aldimines, transition metal-catalyzed chelation-controlled hydrosilylation of α-chloroesters has not previously been described …”

Section: Results and Discussionmentioning

confidence: 99%

Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

et al. 2016

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A new, highly selective, bond functionalization strategy, achieved via relay of two transition metal catalysts and the use of traceless acetal directing groups, has been employed to provide facile formation of C–Si bonds and concomitant functionalization of a silicon group in a single vessel. Specifically, this approach involves the relay of Ir-catalyzed hydrosilylation of inexpensive and readily available phenyl acetates, exploiting disubstituted silyl synthons to afford silyl acetals and Rh-catalyzed ortho-C–H silylation to provide dioxasilines. A subsequent nucleophilic addition to silicon removes the acetal directing groups and directly provides unmasked phenol products and, thus, useful functional groups at silicon achieved in a single vessel. This traceless acetal directing group strategy for catalytic ortho-C–H silylation of phenols was also successfully applied to preparation of multisubstituted arenes. Remarkably, a new formal α-chloroacetyl directing group has been developed that allows catalytic reductive C–H silylation of sterically hindered phenols. In particular, this new method permits access to highly versatile and nicely differentiated 1,2,3-trisubstituted arenes that are difficult to access by other catalytic routes. In addition, the resulting dioxasilines can serve as chromatographically stable halosilane equivalents, which allow not only removal of acetal directing groups but also introduce useful functional groups leading to silicon-bridged biaryls. We demonstrated that this catalytic C–H bond silylation strategy has powerful synthetic potential by creating direct applications of dioxasilines to other important transformations, examples of which include aryne chemistry, Au-catalyzed direct arylation, sequential orthogonal cross-couplings, and late-stage silylation of phenolic bioactive molecules and BINOL scaffolds.

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Section: Results and Discussionmentioning

confidence: 99%

Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

et al. 2016

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“…Due to the increased interest in fluorinated precursors and our recent success in the area of diastereoselective reductions of α‐fluoroimines, α‐fluoro ketones were chosen as the substrate of choice 6. Well established methods for the synthesis of α‐fluoro ketones were used for the preparation of our starting substrates 7.…”

Section: Resultsmentioning

confidence: 99%

Solvent‐Assisted Diastereoselective Trimethylsilyl Cyanide Additions to Cyclic α‐Fluoro Ketones

Pham

Davis

2013

Eur J Org Chem

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“…On the other hand, coordination of alkyl halides to transition metal centers has been known for some time . Examples of chelation-controlled additions to α-halo carbonyl or imino substrates all involve hydride nucleophiles with α-fluoro carbonyl derivatives. − With these ideas in mind, we set out to examine additions of organozinc reagents to α-halo carbonyl compounds . Our initial work with α-halo aldehydes gave very high diastereoselectivities favoring chelation control, but aldehyde reduction products dominated.…”

Section: Chelation-controlled Additions To α-Chloro Aldiminesmentioning

confidence: 99%

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

Fan

Walsh

2017

Acc. Chem. Res.

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The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with α- or β-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral α- and β-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR moiety being both bulky and weakly coordinating, provide anti diols (Felkin addition). It is well-known that exceptions to this paradigm are scarce. Therefore, the choice of PG is based on the desired stereochemical outcome in the addition step and is often inappropriate for the global protection strategy. Thus, it is critical to develop general methods for chelation-controlled additions of organometallics to chiral silyloxy aldehydes and ketones. Once the challenge of developing chelation-controlled additions to silyloxy carbonyl compounds can be met, the next question is what other pendant functional groups can chelate? Herein we introduce the first general methods for the chelation-controlled addition of organometallics to chiral silyloxy aldehydes and ketones. A wide variety of organozinc reagents have been used in these addition reactions, including dialkylzinc reagents that are commercially available or generated using Knochel's methods. Existing protocols for the generation of (E)-di- and -trisubstituted vinylzinc reagents have been employed, and new methods for the generation of (Z)-di- and -trisubstituted vinylzinc reagents have been developed. The generation of 1,1-heterobimetallic reagents based on boron and zinc has been advanced, and the addition of these reagents to silyloxy aldehydes via chelation-control is included. We will first describe the initial discovery and a model to explain the observed diastereoselectivities. A wide array of chelation-controlled additions to chiral α- and β-silyloxy aldehydes and ketones will then be presented. We next describe other functional groups that undergo chelation-controlled additions. α-Halo aldehyde derivatives are well-known to favor Felkin addition (via the Cornforth-Evans model). We introduce a general method for chelation-controlled additions to α-halo aldimines that provides useful precursors to aziridines. Finally, we provide preliminary evidence that even C═C bonds can play the role of chelatin...

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Highly Efficient Diastereoselective Reduction of α-Fluoroimines

Cited by 29 publications

References 50 publications

Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

Solvent‐Assisted Diastereoselective Trimethylsilyl Cyanide Additions to Cyclic α‐Fluoro Ketones

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

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Highly Efficient Diastereoselective Reduction of α-Fluoroimines

Cited by 29 publications

References 50 publications

Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines

Solvent‐Assisted Diastereoselective Tri­meth­ylsilyl Cyanide Additions to Cyclic α‐Fluoro Ketones

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds

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Solvent‐Assisted Diastereoselective Trimethylsilyl Cyanide Additions to Cyclic α‐Fluoro Ketones